Most hormonal contraceptives show little absolute risk of stroke or heart attack, study finds

A recent study found that the absolute risk of increased thrombotic stroke and myocardial infarction (MI) associated with the use of hormonal contraception was low, although the relative risks varied depending on whether higher doses were used.

The 15-year historical cohort study appeared in the June 14 New England Journal of Medicine and followed nonpregnant Danish women ages 15 to 49 with no history of cardiovascular disease or cancer. Data on use of hormonal contraception, clinical end points, and potential confounders were obtained from four national registries.

More than 1.6 million women totaled more than 14 million person-years of observation, during which 3,311 thrombotic strokes (21.4 per 100,000 person-years) and 1,725 MIs (10.1 per 100,000 person-years) occurred.

The case fatality rate during the primary event or subsequent hospital stay was 1% for thrombotic stroke (34 of 3,311 women) and 10.8% for MI (186 of 1,725).

As compared with nonuse, current use of oral contraceptives that included ethinyl estradiol at a dose of 30 to 40 μg was associated with the following relative risks for thrombotic stroke and MI, respectively:

• norethindrone, 2.2 (95% CI, 1.5 to 3.2) and 2.3 (95% CI, 1.3 to 3.9);
• levonorgestrel, 1.7 (95% CI, 1.4 to 2.0) and 2.0 (95% CI, 1.6 to 2.5);
• norgestimate, 1.5 (95% CI, 1.2 to 1.9) and 1.3 (95% CI, 0.9 to 1.9);
• desogestrel, 2.2 (95% CI, 1.8 to 2.7) and 2.1 (95% CI, 1.5 to 2.8);
• gestodene, 1.8 (95% CI, 1.6 to 2.0) and 1.9 (95% CI, 1.6 to 2.3) and
• drospirenone, 1.6 (95% CI, 1.2 to 2.2) and 1.7 (95% CI, 1.0 to 2.6).

With ethinyl estradiol at a dose of 20 μg, the respective relative risks were:

• desogestrel, 1.5 (95% CI, 1.3 to 1.9) for thrombotic stroke and 1.6 for MI (95% CI, 1.1 to 2.1);
• gestodene, 1.7 (95% CI, 1.4 to 2.1) and 1.2 (95% CI, 0.8 to 1.9); and
• drospirenone, 0.9 (95% CI, 0.2 to 3.5) and 0.0.

For transdermal patches, the relative risks were 3.2 for stroke (95% CI, 0.8 to 12.6) and 0.0 for MI; for a vaginal ring, the relative risks were 2.5 for stroke (95% CI, 1.4 to 4.4) and 2.1 for MI (95% CI, 0.7 to 6.5).

For women who smoked compared with those who did not, the relative risks of thrombotic stroke and MI were 1.57 (95% CI, 1.31 to 1.87) and 3.62 (95% CI, 2.69 to 4.87), respectively.

The authors concluded, “We estimate that among 10,000 women who use desogestrel with ethinyl estradiol at a dose of 20 μg for 1 year, 2 will have arterial thrombosis and 6.8 women taking the same product will have venous thrombosis. Although venous thrombosis is three to four times as frequent as arterial thrombosis among young women, the latter is associated with higher mortality and more serious consequences for the survivors. Therefore, these figures should be taken into account when prescribing hormonal contraception.”

An editorial commented that five decades of research show that there is a small risk of arterial thrombotic events in women using combined estrogen-progestin hormonal contraceptives. The already small risk could be further reduced or eliminated by not smoking and by stopping hormonal contraceptive use if blood pressure rises.

“With the addition of the Danish data, evidence is now even stronger that progestin-only formulations of hormonal contraception have vascular risks that are undetectable with modern epidemiologic methods,” the editorial states. “Although hormonal contraception is not risk-free, the evidence is convincing that the low and very low doses of ethinyl estradiol (<50 μg) in the combined estrogen-progestin contraceptives studied by Lidegaard and colleagues—whatever the progestin and whether delivered orally or by means of the patch or the ring—are safe enough.”